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Nitric oxide (NO) is considered a retrograde messenger involved in synaptic plasticity and neurotoxicity (1-3). In the brain, NO is generated by the neuronal, inducible, and endothelial isoforms of nitric oxide synthase (nNOS, iNOS, and eNOS, respectively). nNOS and eNOS are calcium dependent, whereas iNOS, present primarily in microglia and macrophages, is calcium independent. There is a particular interest on the role of nNOS in central nervous system (CNS) pathology because the stimulation of nNOS is associated primarily with the activation of the N-methyl-d-aspartate (NMDA) type of glutamate receptors. The increase of calcium influx caused by NMDA receptor activation leads to binding of calcium to calmodulin, which then stimulates nNOS (1-3). l-arginine is the substrate of NOS; the conversion of l-arginine to l-citrulline causes the release of NO. Several studies have indicated that NO modulates the release of various neurotransmitters such as dopamine, gultamate, and norepinephrine (4-6). Thus, there is a reason to consider NO as a major neuromodulator of synaptic transmission in brain.

Psychostimulants such as cocaine and methamphetamine (METH) cause an increase in synaptic dopamine (DA) level in the caudate nucleus (dorsal striatum) and nucleus accumbens (NAc; ventral striatum). Cocaine binds to the dopamine transporter and blocks the reuptake of DA. Amphetamines not only inhibit the reuptake of DA but also cause further release of DA via reversal of the DA transporter.

Psychostimulant-induced augmentation in extracellular DA level with in the NAc, after repeated administration of the drug, is one leading hypothesis that pertains to psychostimulant-induced behavioral sensitization (7-9). However, other studies have shown persistent behavioral sensitization that coincides with diminished DA response in the NAc (10). In recent years, increasing evidence suggests the involvement of excitatory amino acids (e.g., glutamate and glutamate receptor subtypes) in the induction and expression of sensitization to psychostimulants (11,12). For example, the induction of behavioral sensitization to cocaine and amphetamine appears to involve activation of NMDA and non-NMDA glutamate receptors, as well as DA receptors (13-15; and chapter7).

Because evidence has linked the activation of NMDA receptors to the stimulation of nNOS, we hypothesized that NO is involved in the effects of psychostimulants. To test this hypothesis, we investigated the effect of nNOS inhibitors on (1) the psychomotor-stimulating effect of cocaine and METH, (2) the rewarding effect of cocaine, and (3) the dopaminergic neurotoxicity caused by a high dose of METH. In addition, we investigated the effects of cocaine and METH on mice deficient of the nNOS gene—nNOS knockout mice. Both the pharmacological and genetic manipulation of nNOS support the hypothesis that nNOS plays a major role in the psychomotor-stimulating and rewarding effects of psychostimulants as well as in METH-induced dopaminergic neurotoxicity.

From: Contemporary Clinical Neuroscience: Glutamate and Addiction Edited by: Barbara H. Herman et al. © Humana Press Inc., Totowa, NJ

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